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The Z otarolimus-eluting E ndeavor sprint stent in U ncertain DE S candidates (ZEUS)

The Z otarolimus-eluting E ndeavor sprint stent in U ncertain DE S candidates (ZEUS). M. Valgimigli, MD, PhD Erasmus MC, Rotterdam The Netherlands On behalf of the ZEUS Investigators. Background.

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The Z otarolimus-eluting E ndeavor sprint stent in U ncertain DE S candidates (ZEUS)

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  1. The Zotarolimus-eluting Endeavor sprint stent in Uncertain DES candidates (ZEUS) M. Valgimigli, MD, PhD Erasmus MC, Rotterdam The Netherlands On behalf of the ZEUS Investigators

  2. Background • Drug-eluting stents (DES) reduce restenosis rates and consequently the risk of target vessel failure as compared to bare metal stents (BMS). • However, first generation devices have raised safety concerns due to an higher incidence of stent thrombosis • In order to restore safety to a level comparable to that shown after BMS implantation, a prolonged course of dual antiplatelet therapy (DAPT) has been therefore recommended after DES.

  3. DAPT duration and DES • RCTs comparing DES vs BMS have so far mandated longer DAPT regimen after DES as compared to BMS OR a similarly prolonged course of DAPT in BMS patients (control group) so to match the extended course of therapy after DES • No study has so far disentangled the effects of DES vs BMS from those offered by long-term DAPT • No study has allowed for the shortest possible DAPT duration, i.e. 30 days, after DES, which is the accepted minimum Tx duration after BMS

  4. Background • As a consequence, the use of DES instead of BMS remains controversial in selected patient/lesion subsets: • Pts at high bleeding risk – in whom long-term DAPT poses safety concerns • Pts at high thrombosis risk – whose risk for coronary events may be higher after DES • Pts at low risk for in-stent restenosis – the need for prolonged DAPT and the long-term risk for adverse events after DES implantation may outweigh their benefit in terms of low re-intervention rates Systematically Excluded from RCTs

  5. Zotarolimus-eluting Endeavor Sprint:hydrophilic polymer-based second-generation device with unique drug fast-release profile Drug Elution Kinetics 100 80 ZES (PC-Coating) 100% Eluted at 14days No detectable drug in arterial tissue beyond 28 days 60 Other 1 or 2 gen DES Drug Release (%) 40 E-ZES 20 0 0 0.5 1 2 3 5 7 14 28 60 90 180 Days Zotarolimus in Arterial Tissue (in Stent) 30 25 20 Other 1 or 2 gen DES 15 Zotarolimus (ng/mL) 10 E-ZES 5 0 0 0.5 1 2 3 5 7 14 28 60 90 180 Days EuroInterv.2007;3:50-53

  6. Study Design Am Heart J. 2013 Nov;166(5):831-8 Urgent or emergent coronary stenting in pts fulfilling ≥1 of the below: High Bleeding Risk High Thrombotic Risk Low Restenosis Risk Need for OACs Intolerance to ASA Planned stent ≥3.0 mm, Previous Relevant Bleeding Intolerance to any P2Y12 apart from LMCA and Age > 80 y/o Planned surgery w/in 1 year SVG intervention or for Bleeding diathesis Cancer-life expectancy >1 Y ISR lesions Known Anemia (Hb<10 gr/dl) Pro-thrombotic diathesis Need for CCS or NSAID Rx: 1:1, Sx: inclusion criteria 1,606 pts, 20 sites in Italy, Switzerland, Portugal and Hungary from June 2011 to September 2012 Endeavor Sprint Zotarolimus-eluting Stent Thin-strut Bare Metal Stent Primary Endpoint: Death, Myocardial Infarction or Target Vessel Revascularization at 12 months

  7. Study Design Am Heart J. 2013 Nov;166(5):831-8 Urgent or emergent coronary stenting in pts fulfilling ≥1 of the below: High Bleeding Risk High Thrombotic Risk Low Restenosis Risk Need for OACs Intolerance to ASA Planned stent ≥3.0 mm, Previous Relevant Bleeding Intolerance to any P2Y12 apart from LMCA and Age > 80 y/o Planned surgery w/in 1 year SVG intervention or for Bleeding diathesis Cancer-life expectancy >1 Y ISR lesions Known Anemia (Hb<10 gr/dl) Pro-thrombotic diathesis Need for CCS or NSAID Rx: 1:1, Sx: inclusion criteria 1,606 pts, 20 sites in Italy, Switzerland, Portugal and Hungary from June 2011 to September 2012 Endeavor Sprint Zotarolimus-eluting Stent Thin-strut Bare Metal Stent Personalised DAPT duration, i.e. modelled according to the patient clinical risk profile and not by stent type

  8. Study Design Am Heart J. 2013 Nov;166(5):831-8 Urgent or emergent coronary stenting in pts fulfilling ≥1 of the below: High Bleeding Risk High Thrombotic Risk Low Restenosis Risk Need for OACs Intolerance to ASA Planned stent ≥3.0 mm, Previous Relevant Bleeding Intolerance to any P2Y12 apart from LMCA and Age > 80 y/o Planned surgery w/in 1 year SVG intervention or for Bleeding diathesis Cancer-life expectancy >1 Y ISR lesions Known Anemia (Hb<10 gr/dl) Pro-thrombotic diathesis Need for CCS or NSAID DAPT: Stable CAD 30 days ACS ≥ 6 mos DAPT: None if ASA/P2Y12i intol. Up to surgery if planned ≥ 6 mos in others DAPT: 30 days

  9. Napoli—C. Briguori Szeged— A. Thury, I. Ungi Lisbon— H. M. Gabriel; Szeged— A. Thury, I. Ungi; Torino—S. Colangelo; R. Garbo Parma—A. Menozzi Zingonia—N. de Cesare Ferrara—Sponsor and study site with an unrestricted grant from Medtronic Torino—E. Meliga Baggiovara —S. Tondi Geneva—M. Roffi Arezzo—F. Liistro Clinical Event Committee Milano— L. Testa, F. Bedogni P. Vranckx, Chair S. Curello G. Guardigli Pavia—M. Ferlini Lisbon— H. M. Gabriel Milano—F. Airoldi Data Management and Monitoring Savigliano—A. Dellavalle Medical Trial Analysis Eustrategy Research Coordination Bergamo—G. Musumeci Ravenna—M. Acquilina

  10. Key baseline or angiographic features of the study population (N=1,606) BMS (N=804)E-ZES (N=802) Age, median (IQR) 74 (64-81) 74 (64-81) Females (%) 29 30 Diabetes (%) 26 27 Prior MI/PCI/CABG (%) 24/19/7 24/19/7 Mild to Severe CKD (%) 4142 ACS/STEMI (%) 63/19 63/ 19 MVD (%) 61 59 LAD/LMCA treated (%) 51/5 53/5 ≥1 B2/C treated lesion (%) 73 73 MI: myocardial infarction; PCI: percutaneous coronary intervention; CABG: coronary artery bypass grafting; CKD: chronic kidney dysfunction; Lad: left anterior descending, LMCA: left main coronary artery; ACS: acute coronary syndrome; STEMI: ST-segment elevation myocardial infarction

  11. Study Population High Bleeding Risk 828 (52%) 454 (28%) Low Restenosis Risk -Unstable- 604 (38%) 173 (11%) Low Restenosis Risk -Stable- 337 (21%) 107 (7%) 71 (4%) 14 (1%) 9 (1%) 388 (24%) 199 (12%) 29 (2%) 22 (1%) 140 (9%) High Thrombosis Risk 285 (17%)

  12. ZEUS: Truly high risk patient population Event rates at 1 year across stent trials ≈30% of the screened patient population %

  13. Duration of DAPT* in stent groups (ITT) *: to first planned permanent discontinuation 77.3% 62.5% 43.6% Median: 31 days (IQR: 30-180) Median: 33 days (IQR: 30-180) 37.5% on DAPT 24.7% on DAPT 4.6% 2 Months 6 Months

  14. Major Adverse Cardiovascular events primary endpoint BMS 22.1% 17.5% % E-ZES HR: 0.76 (0.61-0.95), P=0.011 No. at Risk BMS 804 752 716 689 668 651 639 628 E-ZES 802 761 747 723 705 685 673 664 2 pts, one in each group, were lost to follow-up after hospital discharge

  15. Target Vessel Revascularization BMS 10.7% % 5.9% E-ZES HR: 0.53 (0.37-0.75) P<0.001 No. at Risk BMS 804 759 721 694 675 657 645 636 E-ZES 802 765 751 729 712 693 682 675

  16. Myocardial infarction 8.1% BMS % 2.9% E-ZES HR: 0.35 (0.22-0.56), P<0.001 No. at Risk BMS 804 757 730 709 695 684 675 666 E-ZES 802 762 750 733 726 713 698 684

  17. An application of the Classification System from the Universal MI Definition P=0.001 P=0.009 % P=0.11 P=0.13

  18. Definite or Probable Stent Thrombosis BMS 4.1% % 2.0% E-ZES HR: 0.48 (0.27-0.88), P=0.019 No. at Risk BMS 804 763 739 723 712 701 692 685 E-ZES 802 767 758 741 733 721 713 708

  19. Bleeding events in the two groups BARC scale P=N.S. for all comparisons

  20. Subgroup Analysis for the Primary Endpoint HAZARD RATIO (95% CI) No. of patients HAZARD RATIO (95% CI) P-VALUES Interaction 1,606 Overall 0.76 (0.61-0.95) 1,133 Male 0.85 (0.65-1.10) 0.12 473 Female 0.58 (0.38-0.88) 741 > 75 yr 0.82 (0.62-1.10) 0.41 865 ≤ 75 yr 0.68 (0.48-0.96) 420 Diabetes 0.80 (0.54-1.19) 0.74 1,186 0.74 (0.56-0.96) No diabetes 590 Stable coronary disease 0.97 (0.63-1.49) 0.18 1,016 Unstable coronary disease 0.69 (0.53-0.89) 1,077 Protocol mandated no or up to 30 day DAPT 0.75 (0.58-0.96) 0.87 529 Protocol mandated > 30 day DAPT 0.78 (0.49-1.23) 828 High bleeding risk criteria yes 0.74 (0.50-1.09) 0.99 High bleeding risk criteria no 778 0.74 (0.57-0.97) 285 High thrombotic risk criteria yes 1.02 (0.64-1.64) 0.15 1,321 High thrombotic risk criteria no 0.70 (0.54-0.90) 941 Low restenosis risk criteria yes 0.67 (0.48-0.93) 0.30 665 Low restenosis risk criteria no 0.85 (0.63-1.15) 1.8 1 0.2 BMS better E-ZES better

  21. Conclusions • in patients at high bleeding, thrombotic or low restenosis risk, E-ZES implantation followed by a personalized duration of DAPT, including no or a 30-day course of therapy, resulted in a lower risk of major adverse cardiovascular events as compared to BMS • Our study suggests that E-ZES may become the new gold standard coronary device in pts who cannot or refuse to tolerate (long-term) DAPT

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